mTOR抑制剂在癌症治疗中得应用.ppt

mTOR Mammalian Target of Rapamycin (哺乳动物雷帕霉素靶蛋白) mTOR(哺乳动物雷帕霉素靶蛋白) mTOR Pathway Activation mTOR Activation mTOR-Linked Pathway Activation in Selected Cancers Rapamycin (sirolimus)-雷帕霉素 Isolated in 1975 on the island of Rapa Nui Approved for prevention of kidney transplant rejection in the US and Europe Found to have broad anticancer activity against a panel of human cancer cell lines by the U.S. NCI in the 1980s Rapamycin derivatives with improved pharmacokinetic properties →Clinical development of mTOR inhibitors as anticancer agents Clinical Development of mTOR Inhibitors(Derivates of rapamycin ) Temsirolimus (CCI-779, Torisel, Wyeth Pharmaceuticals) Everolimus (RAD001, Afinitor, Novartis) Deforolimus (AP23573, ARIAD Pharmaceuticals and Merck Co) mTOR inhibition: Similar Mechanism of Action mTOR inhibition  (Similar mechanism of action) mTOR Inhibitors: Derivates of Rapamycin Formulation, and administration: different Temsirolimus: Administered Intravenously Deforolimus: administered Intravenously Everolimus: administered Orally mRCC Standards for RCC Therapy by Phase III Trial after ASCO 2007 Everolimus (RAD001) (口服mTOR抑制剂) Everolimus (RAD001, Afinitor) in RCCRationale About 75% of clear cell carcinomas, the function of the von Hippel Lindau (VHL) gene is lost, causing accumulation of HIF (低氧诱导因子)/↑expression of VEGF and PDGF. Other proteins in the PI3K-AKT-mTOR pathway are often deregulated in RCC Unmet medical needs for Patients who have failed VEGFt-TKI therapy Everolimus has both antiangiogenic and antiproliferative activity; response were observed in previously treated mRCC (uncontrolled phase II study) Better Inhibition of p70S6 Kinase With Daily Schedule Phase II Trial of RAD001 in mRCC (Amato) RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) 随机III期试验:比较RAD001与安慰剂 (phase III, double-blind, randomized trial of RAD001+ BSC vs Placebo+BSC) RECORD-1 Phase III study design(随机III期试验:比较RAD001与安慰剂) Progressi